Ceftriaxone is chemically known as (6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino]acetamido]-3-(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid disodium salt hemiheptahydrate.
Ceftriaxone is a cephalosporin antibiotic of a great therapeutic interest due to its effective antibacterial activity in the treatment of several affections and is disclosed in U.S. Pat. No. 4,758,556.
EP 0037 380 describes a process for the preparation of ceftriaxone which starts from 7-amino-3-(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid, which suitably protected at the carboxylic group, is made to react with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-synmethoxymino acetate, then, after being deprotected, it gives ceftriaxone in the form of free acid. Its corresponding transformation into its soluble form as disodium salt is carried out afterwards according to the known techniques.
U.S. Pat. No. 6,552,186 claims a process for the preparation of ceftriaxone which comprises reacting of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl)}-3-cephem-4-carboxylic acid with 4-halo-2(Z)-methoximino-3-oxobutyric acid using a silylating agent in the presence of solvent at a temperature of −10° C. to produce silylated compound and cyclizing the silylated compound with silylated thiourea using a solvent system containing organic solvent and water to obtain ceftriaxone formula (I). This patent also claims a process wherein the silylated (6R,7R)-7-[4-halo-2-[methoxyimino]acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylic acid is desilylated and then reacted with thiourea to produce ceftriaxone of formula (I).
EP 30294 disclosed a process comprising reacting 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl)}-3-cephem-4-carboxylic acid with 4-halo-2(Z)-methoximino-3-oxobutyric acid in the presence of a silylating agent in the presence of solvent to produce (6R,7R)-7-[4-halo-2-[methoxyimino]acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylic acid and reacting with thiourea in the presence of solvent selected from lower alkanol, lower ketone, an ether, DMF, DMAc, water and the like or mixtures thereof to produce ceftriaxone free acid which is then converted to sodium salt of formula (I).
The above-mentioned processes produce ceftriaxone using multi solvent system, which makes the recovery of solvents difficult and also increases the production cost. We focused our research to replace the multi solvent system with single organic solvent in order to reduce the cost of production and improve the purity and yield of the product. Overall, the process is environment friendly because, the solvent used is easily recovered and reused without producing much effluent.
The present invention is based on our observation that the purity and yield of the product can be improved when the reaction is carried out in water as a solvent alone without using multiple solvents.